Layered Pharmaceutical Formulations

ABSTRACT

In one embodiment a layered pharmaceutical formulation includes two or more pharmaceutical layers and an intermediate layer disposed between at least two of the two or more pharmaceutical layers, the intermediate layer configured to dissolve in vivo to thereby leave the two or more pharmaceutical layers substantially intact. In one embodiment, an active pharmaceutical ingredient in at least one of the pharmaceutical layers is selected from bupropion, zonisamide, naltrexone, topiramate, phentermine, metformin, olanzapine and fluoxetine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/541,525, filed Nov. 14, 2014, currently pending, which is acontinuation of U.S. patent application Ser. No. 13/680,922, filed Nov.19, 2012, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 13/330,395, filed Dec. 19, 2011, now U.S. Pat. No.8,318,788, which issued on Nov. 27, 2012, which is a divisional of U.S.patent application Ser. No. 11/937,421, filed Nov. 8, 2007, now U.S.Pat. No. 8,088,786, which issued on Jan. 3, 2012, which claims priorityunder 35 U.S.C. § 119 to U.S. Provisional Application Ser. No.60/865,157, filed Nov. 9, 2006, each of which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to pharmaceutical formulations having two or morepharmaceutical layers interspersed with one or more intermediate layers,wherein the pharmaceutical layers include, but are not limited to,pharmaceutical compositions useful for affecting weight loss,suppressing appetite and/or treating obesity-related conditions inindividuals.

Description of the Related Art

Certain types of layered tablets are known in pharmaceuticalapplications. Some pharmaceutical applications separate potentiallyinteracting layers from one another within a tablet. For example, U.S.Pat. No. 6,576,256 discloses separating potentially interactingcompounds from each other using separate flat layers of a tablet,concentric layers, coated beads or granules, and/or using buffers.Thombre, A. G., L. E. Appel, et al. (2004), “Osmotic drug delivery usingswellable-core technology” J. Control Release 94(1): 75-89 discloses acore tablet containing a drug and a water-swellable component, and oneor more delivery ports in different core configurations including atablet-in-tablet (TNT) bilayer and trilayer formation. U.S. Pat. No.6,706,283 discloses an osmotic delivery device fabricated in a bilayergeometry, wherein the core comprises a sweller layer “sandwiched”between two drug layers. The coating of a bilayer tablet may include awater permeable membrane, but is substantially impermeable to the drugand/or the excipients contained therein. U.S. Pat. No. 6,630,165discloses dosage forms and methods for providing sustained releasereboxetine including a trilayered compressed core with a first componentdrug layer, a second component push layer and a third component barrierlayer separating the drug layer from the push layer. The barrier layeris inert with the respect to the composition of the drug layer andsubstantially impermeable, such that the drug and the components of thepush layer are prevented from mixing.

Among multiple layer tablet forms, one type includes a first layer toprovide immediate release of a drug and a second layer to providecontrolled-release of the drug. U.S. Pat. No. 6,514,531 discloses coatedtrilayer immediate/prolonged release tablets comprising zolpidemhemitartrate. U.S. Pat. No. 6,087,386 discloses a trilayer tablet withan enalapril layer, a losartan potassium layer and a second enalaprilmaleate layer or an excipient layer. U.S. Pat. No. 5,213,807 disclosesan oral trilayer tablet with a core comprising a nonsteroidalanti-inflammatory drug (NSAID), ibuprofen and ibuprofen salts and anintermediate coating comprising a substantially impervious/impermeablematerial to the passage of ibuprofen. U.S. Pat. No. 6,926,907 disclosesa trilayer tablet that separates famotidine contained in a film coatfrom a core comprising controlled-release naproxen formulated usingexcipients which control the drug release. The film coat is an entericcoating configured to delay the release of naproxen until the dosageform reaches an environment where the pH is above four.

SUMMARY

An embodiment provides a layered pharmaceutical formulation comprisingtwo or more pharmaceutical layers and an intermediate layer disposedbetween at least two of the two or more pharmaceutical layers. In someembodiments the intermediate layer is configured to dissolve in vivo tothereby leave the two or more pharmaceutical layers substantiallyintact, but physically separated, essentially forming two distinctpills. In some embodiments the dissolution rate of one of the separatedtwo or more pharmaceutical layers is substantially similar to that of asingly compressed tablet comprising the same pharmaceutical compositionas that of the pharmaceutical layer.

Use of a first compound and a second compound in the preparation of amedicament for affecting weight loss, suppressing appetite and/ortreating an obesity-related condition, wherein the medicament compriseslayered pharmaceutical formulations of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Other aspects of the disclosure will be readily apparent from thedescription below and the appended drawings, in which like referencenumerals refer to similar parts throughout, which are meant toillustrate and not to limit the disclosure, and in which:

FIG. 1A illustrates an embodiment of a layered pharmaceuticalformulation.

FIGS. 1B & 1C illustrate the layered pharmaceutical formulation of FIG.1A in progressive stages as an intermediate layer dissolves.

FIG. 2A illustrates a second embodiment of a layered pharmaceuticalformulation.

FIG. 2B illustrates the second embodiment of FIG. 2A after anintermediate layer dissolves.

FIG. 3 illustrates a third embodiment of a layered pharmaceuticalformulation.

FIG. 4 illustrates a fourth embodiment of a layered pharmaceuticalformulation.

FIG. 5 illustrates a fifth embodiment of a layered pharmaceuticalformulation with multiple intermediate layers.

FIG. 6 illustrates a sixth embodiment of a layered pharmaceuticalformulation with lenticular shaped layers.

FIG. 7 illustrates a seventh embodiment of a layered pharmaceuticalformulation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Embodiments of the present disclosure provide significant improvementsto multilayer tablet technology. In an embodiment, a layeredpharmaceutical formulation comprises two or more pharmaceutical layersand at least one intermediate layer disposed between at least two of thetwo or more pharmaceutical layers. The at least one intermediate layeris configured to dissolve in vivo to thereby leave the two or morepharmaceutical layers substantially intact. In some embodiments thedissolution rate of one or more of a separated pharmaceutical layer issubstantially similar to that of a singly compressed tablet comprisingthe same pharmaceutical composition as that of the pharmaceutical layer.The separated pharmaceutical layer thus has an independent andpredictable dissolution profile.

A dissolution profile for a drug comprises the known dissolution rateand particular dissolution characteristics of the drug. A predictabledissolution profile for a specific drug allows for more accuratetreatment of a given symptom. Predictable dissolution profiles fordifferent drugs within a multilayer tablet allow for coordinatedtreatment of multiple symptoms with a single pharmaceutical formulation.

In general, multilayer pharmaceutical formulations present challenges inmaintaining predictable dissolution profiles. For example, in vivoconditions often disrupt an otherwise predictable multilayerpharmaceutical formulation dissolution profile. A multilayer tablet maybe manufactured with drugs of known dissolution profiles. Once themultilayer tablet is ingested by a patient, however, there is noguarantee that each drug will dissolve as predicted by its individualdissolution profile. Drug configuration within a tablet, tablet shape,excipients or fillers in the tablet, tablet coatings and in vivoconditions may all affect the dissolution profiles. Additionally,interaction between different drugs within a multilayer tablet may causea change in dissolution profile for one or more compositions within themultilayer tablet.

Further, in one possible in vivo condition, if the multilayer tabletbecomes attached to the lining of the stomach, only a portion of thetablet would be exposed to the stomach fluids. The dissolution of theexposed portion of the tablet may occur at a more predictable rate whilethe unexposed portion of the multilayer tablet shielded from the stomachfluids would have a longer dissolution profile than would otherwise beexpected from a singly compressed tablet of an identical composition. Asmentioned above, having a multilayer tablet is desirable for ease ofadministration of multiple pharmaceutical compositions within a singletablet. Thus, it is desirable to configure a multilayer pharmaceuticalformulation such that each pharmaceutical layer has a predictabledissolution profile.

Herein disclosed is a pharmaceutical formulation comprising two or morepharmaceutical layers and at least one intermediate layer configured todissolve in vivo to thereby leave the two or more pharmaceutical layerssubstantially intact. In preferred embodiments the dissolution rate ofone or more of the separated pharmaceutical layers is substantiallysimilar to that of a singly compressed tablet comprising the samepharmaceutical composition as that of the pharmaceutical layer. In someembodiments, the pharmaceutical layer comprises a singlepharmaceutically active compound or drug. In other embodiments thepharmaceutical layer comprises a pharmaceutical composition. The term“pharmaceutical composition” refers to a mixture of a chemical compoundor compounds (e.g., a drug or drugs) with additional pharmaceuticalcomponents, such as diluents or carriers. Herein, the term “drug” issynonymous with the term “pharmaceutically active ingredient.” Thepharmaceutical composition facilitates administration of the drug to anorganism. Pharmaceutical compositions can also be obtained in the formof pharmaceutically acceptable salts by reacting drug compounds withinorganic or organic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

In some embodiments the two or more pharmaceutical layers comprise oneor more immediate-release formulations. The term “immediate-release” isused herein to specify that the immediate release formulation is notconfigured to alter the dissolution profile of the pharmaceutical layer.For example, an immediate release pharmaceutical layer may be apharmaceutical composition that does not contain ingredients includedfor the purpose of altering the dissolution profile. In some embodimentsthe two or more pharmaceutical layers comprise one or morecontrolled-release formulations. The term “controlled-release” is usedherein in its ordinary sense and thus includes pharmaceuticalcompositions combined with ingredients to alter their dissolutionprofile. A “sustained-release” formulation is a type ofcontrolled-release formulation, wherein ingredients have been added to apharmaceutical composition such that the dissolution profile is extendedover a longer period of time than that of an immediate releaseformulation comprising a similar pharmaceutical composition.

In some embodiments the at least one intermediate layer is a flat layerseparating at least two pharmaceutical layers. In some embodiments theat least one intermediate layer has exposed edges. Exposed edges allowfor fluid to contact and dissolve the at least one intermediate layer.In some embodiments the pharmaceutical formulations comprises a coatingcovering the two or more pharmaceutical layers and the at least oneintermediate layer. The coating is configured to dissolve in vivo moreor less uniformly over the two or more pharmaceutical layers and the atleast one intermediate layer such that the at least one intermediatelayer is left exposed to the fluids that will dissolve the at least oneintermediate layer in vivo.

In some embodiments the at least one intermediate layer is or comprisesan impermeable membrane. In some embodiments the at least oneintermediate layer has a substantially higher dissolution rate than atleast one of the pharmaceutical layers. In some preferred embodimentsthe at least one intermediate layer dissolves in a nearly immediatefashion with respect to the dissolution of at least one of thepharmaceutical layers. In some embodiments the at least one intermediatelayer comprises at least one of a monosaccharide or a disaccharidesugar, a starch (e.g., corn or potato starches), or any other suitabletablet ingredients known in the art. In some preferred embodiments theat least one intermediate layer comprises lactose. In some preferredembodiments, the intermediate layer dissolves in a nearly immediatefashion as compared to the dissolution rates of the respectivepharmaceutical layers, e.g., such that upon dissolution of theintermediate layer, substantially all of the surface area of each of thetwo pharmaceutical layers is exposed. Thus, in one embodiment, under astandard dissolution test the immediate release layer is dissolved tothe extent that at least two pharmaceutical layers present in thepharmaceutical formulation are separated in less than 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25or 30 minutes.

Pharmaceutical formulations of drugs can be configured in various waysand in a variety of dosage forms to modify a dissolution rate of thedrug. For example, one type of controlled-release pharmaceuticalformulation is a sustained-release pharmaceutical formulation.Sustained-release pharmaceutical formulations can contain a variety ofexcipients, such as retardant excipients (also referred to as releasemodifiers) and/or fillers that are selected and incorporated into theformulation in such a way as to slow the dissolution rate of theformulation (and thereby slow the dissolution and/or release of thezonisamide) under in vivo conditions as compared to an otherwisecomparable immediate-release formulation. Thus, a “comparable”immediate-release formulation is one that is substantially identical tothe controlled-release formulation, except that that it is configured toprovide immediate-release instead of controlled-release undersubstantially identical conditions.

The term “immediate-release” is used herein to specify a formulationthat is not configured to alter the dissolution profile of the activeingredient (e.g., zonisamide, bupropion, naltrexone, olanzapine,phentermine, topiramate, metformin, fluoxetine). For example, animmediate-release pharmaceutical formulation may be a pharmaceuticalformulation that does not contain ingredients that have been includedfor the purpose of altering the dissolution profile. Animmediate-release formulation thus includes drug formulations that takeless than 30 minutes for substantially complete dissolution of the drugin a standard dissolution test. A “standard dissolution test,” as thatterm is used herein, is a test conducted according to United StatesPharmacopeia 24th edition (2000) (USP 24), pp. 1941-1943, usingApparatus 2 described therein at a spindle rotation speed of 100 rpm anda dissolution medium of water, at 37° C., or other test conditionssubstantially equivalent thereto. The term “controlled-release” is usedherein in its ordinary sense and thus includes pharmaceuticalformulations that are combined with ingredients to alter theirdissolution profile. A “sustained-release” formulation is a type ofcontrolled-release formulation, wherein ingredients have been added to apharmaceutical formulation such that the dissolution profile of theactive ingredient is extended over a longer period of time than that ofan otherwise comparable immediate-release formulation. Acontrolled-release formulation thus includes drug formulations that take30 minutes or longer for substantially complete dissolution of the drugin a standard dissolution test, conditions which are representative ofthe in vivo release profile.

A pharmaceutical layer may be configured in various ways. For example,in some embodiments a layer comprises a flat portion of a pharmaceuticalformulation. In some embodiments a layer comprises a rounded portion ofa pharmaceutical formulation. In some embodiments a layer comprises aconical section of a pharmaceutical formulation. In some embodiments alayer comprises an elliptical section of a pharmaceutical formulation.In some embodiments a layer comprises a sideways section of apharmaceutical formulation. In some embodiments a layer comprises acubical section of a pharmaceutical formulation. In some embodiments alayer comprises a wedge of a pharmaceutical formulation. In someembodiments a layer comprises a substantial portion of a pharmaceuticalformulation. A substantial portion is preferably at least about 25% ofthe pharmaceutical formulation and more preferably at least about 50% ofthe pharmaceutical formulation.

In some embodiments at least one pharmaceutical layer reacts whenbrought into contact with another of the pharmaceutical layers withinthe layered pharmaceutical formulation. In some embodiments at least onepharmaceutical layer does not react when brought into contact withanother of the pharmaceutical layers.

In some embodiments an intermediate layer is configured to dissolve invivo. Dissolving is the act of solvation wherein a solute is dissolvedin a solvent to create a solution. Dissolving in vivo means that thedissolving takes place within an organism or within living tissue eithertaken from or part of an organism. An organism is any living animal,plant, bacteria or fungus. In preferred embodiments the organism ishuman.

In some embodiments a dissolving intermediate layer separates at leasttwo of the pharmaceutical layers. In some embodiments the twopharmaceutical layers contain different pharmaceutical compositions. Insome embodiments after the intermediate layer dissolves, thepharmaceutical layers are no longer held together within thepharmaceutical formulation. In some embodiments after the intermediatelayer dissolves, the pharmaceutical layers remain substantially intact.A pharmaceutical layer remains substantially intact when it retains atleast about 50% of its original mass in a single entity post-dissolutionof the one or more intermediate layers. In preferred embodiments thepharmaceutical layer remains substantially intact when it retains atleast about 75% of its original mass post-dissolution of the one or moreintermediate layers. In more preferred embodiments the pharmaceuticallayer remains substantially intact when it retains at least about 85% ofits original mass post-dissolution of the one or more intermediatelayers. In some embodiments each pharmaceutical layer has a differentdissolution rate. A dissolution rate is the solvation of apharmaceutical layer volume per unit time. In some embodiments one ormore pharmaceutical layers have similar dissolution rates. Preferablythe one or more intermediate layers have a higher dissolution rate thanthe two or more pharmaceutical layers.

FIG. 1A illustrates a preferred embodiment of a pharmaceuticalformulation 100. The pharmaceutical formulation 100 comprises twopharmaceutical layers 102A and 102B. Pharmaceutical layer 102A comprisesa pharmaceutical composition. In some embodiments of the pharmaceuticalformulation 100, the pharmaceutical layer 102B comprises the samepharmaceutical composition as that of the pharmaceutical layer 102A. Inthe illustrated embodiment of pharmaceutical formulation 100, thepharmaceutical layer 102A comprises a different pharmaceuticalcomposition than that of the pharmaceutical layer 102B. Thepharmaceutical formulation 100 also comprises an intermediate layer 106.In the illustrated embodiment the intermediate layer 106 is configuredto dissolve in vivo.

Each of the pharmaceutical layers 102A and 102B comprises one or morepharmaceutical compositions. As illustrated in the pharmaceuticalformulation 100, the dosage amount of each pharmaceutical layer 102A and102B is similar. The dosage strength of each pharmaceutical layer mayalso be similar. In other embodiments the dosage amount and/or strengthof one pharmaceutical layer is much greater than that of another layer.This difference in dosage amount or strength allows for individualizedtreatment of symptoms that are addressed by increasing or decreasing adosage of one or more pharmaceutical layers while maintaining a dosageof other layers. The amount or strength of dosage of a drug containedwithin a pharmaceutical formulation will, of course, be dependent on thesubject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The illustrated pharmaceutical formulation 100 includes, but is notlimited to, drugs for affecting weight loss, suppressing appetite and/ortreating an obesity-related condition in a patient. Specifically, theillustrated pharmaceutical layer 102A comprises zonisamide and thepharmaceutical layer 102B comprises bupropion. The intermediate layer106 comprises lactose or a suitable monosaccharide sugar, disaccharidesugar or a starch. In another embodiment, one or more of thepharmaceutical layers comprises naltrexone, one or more of thepharmaceutical layers comprises bupropion, and at least one intermediatelayer comprises a monosaccharide sugar, a disaccharide sugar or astarch. In another embodiment, one or more of the pharmaceutical layerscomprises naltrexone, one or more of the pharmaceutical layers compriseszonisamide, and at least one intermediate layer comprises amonosaccharide sugar, a disaccharide sugar or a starch. In anotherembodiment, one or more of the pharmaceutical layers comprisesnaltrexone, one or more of the pharmaceutical layers comprisesfluoxetine, and at least one intermediate layer comprises amonosaccharide sugar, a disaccharide sugar or a starch. In anotherembodiment, one or more of the pharmaceutical layers comprisesolanzapine, one or more of the pharmaceutical layers compriseszonisamide, and at least one intermediate layer comprises amonosaccharide sugar, a disaccharide sugar or a starch. In anotherembodiment, one or more of the pharmaceutical layers comprisesmetformin, one or more of the pharmaceutical layers compriseszonisamide, and at least one intermediate layer comprises amonosaccharide sugar, a disaccharide sugar or a starch. In anotherembodiment, one or more of the pharmaceutical layers comprisesphentermine, one or more of the pharmaceutical layers comprisestopiramate, and at least one intermediate layer comprises amonosaccharide sugar, a disaccharide sugar or a starch.

In some embodiments the presence of one drug in a pharmaceuticalformulation enhances the desired physiological effects and/or reducesundesired physiological effects of one or more other drugs in thepharmaceutical formulation. In some embodiments the presence of one ormore drugs in a pharmaceutical formulation enhances the desiredphysiological effects of the drugs over the additive physiologicaleffects of the one or more drugs in comparable, but separatepharmaceutical formulations when administered alone.

FIG. 1B illustrates the pharmaceutical formulation 100 of FIG. 1A as afluid, as represented by the arrow 108, begins to dissolve theintermediate layer 106. In the illustrated embodiment, the fluidcomprises at least one bodily fluid selected from saliva, sweat, chyme,mucus and bile. As the intermediate layer 106 dissolves thepharmaceutical layers 102A and 102B begin to separate as shown. As notedabove, in some embodiments each pharmaceutical layer comprises the samepharmaceutical composition. However, in the illustrated embodiment, thepharmaceutical layers 102A and 102B each comprise a differentpharmaceutical composition. In some embodiments, one or more of thepharmaceutical layers comprises a controlled-release formulation. Insome embodiments, one or more of the controlled-release formulationscomprises a sustained-release formulation.

FIG. 1C illustrates the layered pharmaceutical formulation 100 of FIG.1A after the intermediate layer 106 has completely dissolved. Thepharmaceutical layers 102A and 102B have separated and remainsubstantially intact.

FIG. 2A illustrates an embodiment of a second layered pharmaceuticalformulation 200. The second pharmaceutical formulation 200 comprisessecond pharmaceutical layers 202A, 202B and 202C. In some embodimentstwo or more of the second pharmaceutical layers 202A, 202B and 202Ccomprise the same pharmaceutical composition. In the illustratedembodiment each of the pharmaceutical layers 202A, 202B and 202Ccomprises a different pharmaceutical composition. The secondpharmaceutical formulation 200 also comprises an intermediate layer 106configured to dissolve in vivo.

FIG. 2B illustrates the second layered pharmaceutical formulation 200 ofFIG. 2A. The fluid, as represented by the arrow 108, has dissolved anintermediate layer 106 and the second pharmaceutical layers 202A, 202Band 202C are separated and left substantially intact.

FIG. 3 illustrates an embodiment of a third layered pharmaceuticalformulation 300. The third pharmaceutical formulation 300 comprisesthird pharmaceutical layers 302A, 302B and 302C separated by anintermediate layer 106. Each of the third pharmaceutical layers 302A,302B and 302C comprises one or more pharmaceutical compositions. Asillustrated in the third layered pharmaceutical formulation 300, thethird pharmaceutical layer 302A comprises a similar dosage volume to thethird pharmaceutical layer 302B. The third pharmaceutical layer 302C,however, comprises a larger dosage volume than third pharmaceuticallayers 302A or 302B. As noted above with regard to FIG. 1 , varyingdosage amounts or strengths of particular pharmaceutical layers within apharmaceutical formulation allows for individualized treatment ofparticular symptoms.

FIG. 4 illustrates an embodiment of a fourth layered pharmaceuticalformulation 400. The fourth pharmaceutical formulation 400 includes, butis not limited to fourth pharmaceutical layers 402A and 402B and anintermediate layer 106. The fourth pharmaceutical layer 402A comprises afirst drug 404A and a second drug 404B. The first drug 404A and thesecond drug 404B are positioned within the fourth pharmaceutical layer402A so as to be in physical contact with the other; no intermediatelayer 106 separates the first drug 404A from the second drug 404B withinthe layer 402A. Similarly, the fourth pharmaceutical layer 402Bcomprises a third drug 404C and a fourth drug 404D; no intermediatelayer 106 separates the third drug 404C and the fourth drug 404D.

In the fourth pharmaceutical formulation 400 the intermediate layer 106is disposed between fourth pharmaceutical layers 402C and 402B. In thisembodiment, the edges of intermediate layer 106 are not aligned with thefourth pharmaceutical layers 402C and 402B. A space 408 allows forfluids to interact with and dissolve the intermediate layer 106. Thus,although the intermediate layer 106 is not flush with the outside edgeof the fourth pharmaceutical formulation 400, the intermediate layer 106is exposed for purposes of dissolution upon contact with bodily fluids.

FIG. 5 illustrates an embodiment of a fifth layered pharmaceuticalformulation 500 depicted after separation has occurred. The fifthpharmaceutical formulation 500 includes, but is not limited to fifthpharmaceutical layers 502A and 502B. The fifth pharmaceutical layers502A and 502B each include, but are not limited to one or morepharmaceutical compositions.

The fifth pharmaceutical formulation 500 further comprises a firstintermediate layer 506A and a second intermediate layer 506B. In someembodiments the first intermediate layer 506A is configured tophysically and chemically separate the fifth pharmaceutical layers 502Aand 502B. In some embodiments the second intermediate layer 506B isconfigured to physically and chemically separate the fifthpharmaceutical layers 502A and 502B. The first intermediate layer 506Aand the second intermediate layer 506B each comprise one or moreformulations configured to dissolve in vivo.

FIG. 6 illustrates an embodiment of a sixth layered pharmaceuticalformulation 600. The sixth pharmaceutical formulation 600 includes, butis not limited to sixth pharmaceutical layers 602A and 602B and anintermediate layer 106. The sixth pharmaceutical formulation 600 isconfigured in a lenticular shape, wherein each pharmaceutical layer 602Aand 602B comprises a single convex shape.

Pharmaceutical layers may be configured in various shapes. For example,pharmaceutical layers may be configured in elliptical shapes, sphericalshapes, oblong shapes, square shapes or flat shapes. In some embodimentspharmaceutical formulations are combined with fillers or excipients andplaced in tablets, granules or capsules for later administration. Insome embodiments the tablets are configured in spherical, elliptical,lenticular or capsule shapes.

FIG. 7 illustrates another embodiment of a seventh layeredpharmaceutical formulation 700. The seventh pharmaceutical formulation700 includes, but is not limited to seventh pharmaceutical layers 702A,702B, 702C, 702D, 702E and 702F. Each seventh pharmaceutical layer 702A,702B, 702C, 702D, 702E and 702F comprises one or more pharmaceuticalcompositions. Each seventh pharmaceutical layer 702A, 702B, 702C, 702D,702E and 702F is in a wedge shape. The seventh pharmaceuticalformulation 700 additionally comprises an intermediate layer 106disposed between seventh pharmaceutical layers 702B, 702C and 702D andalso between seventh pharmaceutical layers 702A, 702F and 702E. Asdescribed above the intermediate layer 106 is configured to dissolve invivo upon contact with a certain type of bodily fluid. The seventhpharmaceutical formulation 700 additionally comprises a specialintermediate layer 706 disposed between seventh pharmaceutical layers702A and 702B and between seventh pharmaceutical layers 702D and 702E.The special intermediate layer 706 is configured to dissolve underbodily conditions different than those conditions that dissolveintermediate layer 106. Upon dissolution of the special intermediatelayer 706, the seventh pharmaceutical layers 702A and 702B and theseventh pharmaceutical layers 702D and 702E are left substantiallyintact.

For example, if intermediate layer 106 were configured to dissolve underthe acidic conditions of the stomach in a human patient, specialintermediate layer 706 may be configured to dissolve only after thepharmaceutical formulation 700 reaches the duodenum. In some embodimentsat least one of the pharmaceutical layers comprises an enteric coating.

Manufacture of Pharmaceutical Formulations

As noted above, pharmaceutical formulations may be configured in variousshapes and sizes for ease of administration to a patient. Manufacture ofpharmaceutical formulations configured in tablets comprises steps knownin the art. For example, tablets may be prepared throughwet-granulation, dry-granulation or direct compression. Layeredpharmaceutical formulations may be configured in tablet form in asimilar manner. To manufacture each pharmaceutical layer, one or moredrugs are obtained in, for example, a crystalline, amorphous or powderedform, and mixed with or without diluents and/or excipients into a solidwith pressure. The solid pharmaceutical layer is added with otherpharmaceutical layers and/or intermediate layers and configured in adesired tablet geometry with pressure.

In some embodiments pharmaceutical formulations include, but are notlimited to, one or more of polyvinylpyrrolidine (polyvinylpyrrolidone),hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC),methyl cellulose (MC), vinyl acetate/crotonic acid copolymers,methacrylic acid copolymers (Eudragit), maleic anhydride/methyl vinylether copolymers.

In some embodiments pharmaceutical formulations include, but are notlimited to controlled-release formulations. In some embodiments thecontrolled-release formulations include, but are not limited tosustained-release formulations.

Pharmaceutical Formulations to Treat Obesity

In some embodiments the layered pharmaceutical formulation may be usedto treat obesity. Obesity is a disorder characterized by theaccumulation of excess fat in the body. Obesity has been recognized asone of the leading causes of disease and is emerging as a globalproblem. Increased instances of complications from obesity, such ashypertension, non-insulin-dependent diabetes mellitus, arteriosclerosis,dyslipidemia, certain forms of cancer, sleep apnea and osteoarthritis,have been related to increased instances of obesity in the generalpopulation.

Prior to 1994, obesity was generally considered a psychological problem.The discovery of the adipostatic hormone leptin in 1994 brought forththe realization that in certain cases, obesity may have a biochemicalbasis. The corollary to this realization was the idea that treatment ofobesity may be achieved by chemical approaches. Since then, a number ofsuch chemical treatments have entered the market.

Various methods of affecting weight loss, suppressing appetite and/ortreating an obesity-related condition in a patient involve administeringcertain drugs or combinations thereof. For example, a number ofreferences disclose the administration of certain weight lossformulations that include an anticonvulsant, an opioid antagonist and/ora norepinephrine reuptake inhibitor (NRI) to a patient in need thereofto affect weight loss. See, for example, U.S. Patent ApplicationPublication Nos. 2004/0033965; 2004/0198668; 2004/0254208; 2005/0137144;2005/0143322; 2005/0181070; 2005/0215552; 2005/0277579; 2006/0009514;2006/0142290; 2006/0160750 and 2006/0079501, all of which are herebyincorporated by reference in their entireties. Weight gain has been amajor concern with certain of the newer antidepressants, particularly,with paroxetine (PAXIL® PAXIL CR®) and mirtazapine (Fava, J. Clin.Psych. 61 (suppl. 11):37-41 (2000); Carpenter et al, J. Clin. Psych.60:45-49 (1999); Aronne et al, J. Clin. Psych. 64 (suppl. 8):22-29(2003), both of which are incorporated by reference herein in theirentirety).

Other descriptions of bupropion, zonisamide, controlled-releasezonisamide and combinations thereof are disclosed in U.S ProvisionalPatent Application Nos. 60/740,034, filed on Nov. 28, 2005; 60/832,110,filed on Jul. 19, 2006; 60/835,564, filed on Aug. 4, 2006; and U.S.patent application Ser. No. 11/194,201 entitled COMBINATION OF BUPROPIONAND A SECOND COMPOUND FOR AFFECTING WEIGHT LOSS, filed on Aug. 1, 2005;all of which are hereby incorporated by reference in their entireties.

For methods of administering pharmaceutical compositions useful foraffecting weight loss, suppressing appetite and/or treatingobesity-related conditions in individuals controlled-releaseformulations help to suppress some if not all of the negative sideeffects that may arise from administration of such medication. Even incontrolled-release formulations, however, the administration of certainanticonvulsants or opioid receptor antagonists at a full dosage mayinitially incur severe adverse side effects. Thus, at least initially,patients may be unable to tolerate a full dosage of the prescribed drug,which may include, but is not limited to an anticonvulsant or an opioidreceptor antagonist. This intolerance may lead to more severe sideeffects and/or premature abandonment of the medication and/or thetreatment program.

Administering combinations of drugs, for example, a combinationincluding, but not limited to an anticonvulsant or an opioid receptorantagonist in combination with an antidepressant may enhance the abilityof the anticonvulsant to affect weight loss, but does not necessarilyeliminate the initial adverse side effects that may accompany theadministration of the anticonvulsant or the opioid receptor antagonist.In some embodiments a system comprises a layered pharmaceutical forminimizing side effects during treatment of obesity. In some embodimentsa method comprises administering a layered pharmaceutical formulationcomprising an anticonvulsant or the opioid receptor antagonist to affectweight loss while minimizing or eliminating the initial adverse sideeffects on the patient.

Thus, some preferred embodiments, the layered pharmaceutical formulationis useful for the treatment of obesity and/or for affecting weight loss.Some preferred embodiments comprise at least one of an antidepressantand an anticonvulsant. Other preferred embodiments comprise at least oneof an antidepressant and an opioid receptor antagonist. Other preferredembodiments comprise at least one of an anticonvulsant and an opioidreceptor antagonist. Other preferred embodiments comprise at least oneof an anticonvulsant and an antidiabetic.

Antidepressants and Psychotherapeutics

In some embodiments an antidepressant comprises a dopamine reuptakeinhibitor or receptor antagonist. Examples of dopamine reuptakeinhibitors include, but are not limited to phentermine andpharmaceutically acceptable salts or prodrugs thereof. Examples ofdopamine receptor antagonists include, but are not limited tohaloperidol, ocaperidone, risperidone, olanzapine, quetiapine,amisulpride, and pimozide and pharmaceutically acceptable salts orprodrugs thereof. In some embodiments the antidepressant comprises anorepinephrine reuptake inhibitor. Examples of norepinephrine reuptakeinhibitors include, but are not limited to bupropion, thionisoxetine,atomoxetine and reboxetine and pharmaceutically acceptable salts orprodrugs thereof. Other embodiments include, but are not limited tothose in which the antidepressant is a dopamine agonist. Dopamineagonists available on the market include cabergoline, amantadine,lisuride, pergolide, ropinirole, pramipexole, and bromocriptine. In someembodiments the antidepressant comprises a serotonin reuptake inhibitor.Examples of serotonin reuptake inhibitors include, but are not limitedto fluoxetine and pharmaceutically acceptable salts or prodrugs thereof

Throughout the disclosure of the present specification the term“pharmaceutically acceptable salt” refers to a formulation of a compoundthat does not cause significant irritation to an organism to which it isadministered and does not abrogate the biological activity andproperties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the disclosure with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the disclosure witha base to form a salt such as ammonium salt, an alkali metal salt suchas a sodium or a potassium salt, an alkaline earth metal salt such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl) methylamineand salts thereof with amino acids such as arginine, lysine and thelike.

The term “prodrug” refers to an agent that is converted into the parentdrug in vivo. Prodrugs are often useful because, in some situations,they are easier to administer than the parent drug. They can, forinstance, be bioavailable by oral administration whereas the parent isnot. The prodrug can also have improved solubility in pharmaceuticalcompositions over the parent drug or can demonstrate increasedpalpability or be easier to formulate.

An example, without limitation, of a prodrug would be a compound of thepresent disclosure which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to provide the active moiety.

Bupropion, whose chemical name is(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is theactive ingredient in the drugs marketed as ZYBAN® and WELLBUTRIN®, andis usually administered as a hydrochloride salt. Throughout the presentdisclosure, whenever the term “bupropion” is used, it is understood thatthe term encompasses bupropion as a free base, or as a physiologicallyacceptable salt thereof, or as a bupropion metabolite or salt thereof.

The metabolites of bupropion suitable for inclusion in the methods andcompositions described herein include the erythro- and threo-aminoalcohols of bupropion, the erythro-amino diol of bupropion, andmorpholinol metabolites of bupropion. In some embodiments, themetabolite of bupropion is(±)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. In someembodiments the metabolite is(−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, while inother embodiments, the metabolite is (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol. Preferably, themetabolite of bupropion is(+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol, which isknown by its common name of radafaxine. The scope of the presentdisclosure includes the above-mentioned metabolites of bupropion as afree base or as a physiologically acceptable salt thereof.Controlled-release bupropion formulations of bupropion are known in theart. For example, U.S. Pat. No. 6,905,708 discloses a once-daily dosageconfigured to deliver bupropion in vivo over a 6 to 12 hour period.

Olanzapine, whose chemical name is2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine,is used as a psychotherapeutic agent primarily for the treatment ofschizophrenia, acute manic episodes in bipolar disorder acute,maintenance treatment in bipolar disorder and agitation associated withboth these disorders. Throughout the present disclosure, whenever theterm “olanzapine” is used, it is understood that the term encompassesolanzapine as a free base, or as a physiologically acceptable saltthereof, or as a olanzapine metabolite or salt thereof.

Olanzapine displays linear kinetics. Its elimination half-life rangesfrom 21 to 54 hours. Steady state plasma concentrations are achieved inabout a week. Olanzapine undergoes extensive first pass metabolism andbioavailability is not affected by food.

The psychotherapeutic agent may be selected from the group consisting ofmirtazapine, setiptiline, paroxetine, venlafaxine, olanzapine,bupropion, risperidone, lamotrogine, risperidone, a lithium salt,valproic acid, and pharmaceutically acceptable salts or prodrugsthereof. In some embodiments the psychotherapeutic agent is anantidepressant, an antimigrane, an antibipolar, an antimania drug, amood stabilizer, or an antiepileptic. Examples of antidepressantsinclude paroxetine, mirtazapine, and bupropion. Examples of antibipolardrugs include lithium, valproate, carbamezepine, oxycarbamezepine,lamotrogine, tiagabine, olanzapine, clozapine, risperidone, quetiapine,aripiprazole, ziprasidone, and benzodiazepines. Also included arepharmaceutically acceptable salts or prodrugs of these drugs, extendedrelease or controlled release formulations of the above drugs, as wellas combinations of the above drugs.

Fluoxetine is a selective serotonin reuptake inhibitor (S SRI), whosechemical name isN-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine, is usedprimarily for the treatment of depression (including pediatricdepression), obsessive-compulsive disorder (in both adult and pediatricpopulations), bulimia nervosa, panic disorder, premenstrual dysphoricdisorder, hypochondriasis and body dysmorphic disorder. Throughout thepresent disclosure, whenever the term “fluoxetine” is used, it isunderstood that the term encompasses fluoxetine as a free base, or as aphysiologically acceptable salt thereof, or as a fluoxetine metaboliteor salt thereof.

Fluoxetine has a bioavailability of approximately 72%, and peak plasmaconcentrations are reached in 6 to 8 hours. It is highly bound to plasmaproteins, mostly albumin. Its elimination half-life ranges from 1 to 3days—after a single dose—to 4 to 6 days (after long-term use) in healthyadults, and is prolonged in those with liver disease. The half-life ofnorfluoxetine is longer (16 days after long-term use). Completeexcretion of the drug may take several weeks.

The SSRI can be selected from fluoxetine, fluvoxamine, sertraline,paroxetine, citalopram, escitalopram, sibutramine, duloxetine, andvenlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.In some embodiments, the SSRI is fluoxetine or a pharmaceuticallyacceptable salt or prodrug thereof.

Fluoxetine has a physiological half life of about 24 hours, whereas thatof naltrexone is about 1.5 hours. However their metabolites maydemonstrate half-lives in excess of 24 hours. Thus, in some cases, itmay be beneficial to administer one dose of fluoxetine per day inconjunction with two or three or more doses of naltrexone throughout theday. Naltrexone may also be in a time-release formulation where the doseis administered once a day, but naltrexone gradually enters the bloodstream throughout the day, or in the course of a 12 hour period.

Symptoms of the obsessive compulsive disorders are inhibited inindividuals being administered fluoxetine and naltrexone. Adverse eventsassociated with the obsessive compulsive disorders are reduced inindividuals being administered fluoxetine and naltrexone. The effects ofadministration of both fluoxetine and naltrexone on obsessive compulsivedisorder are synergistic compared to effects of those expected byadministration of fluoxetine and naltrexone alone.

Newer generation antidepressants include selective serotonin reuptakeinhibitors (e.g., fluoxetine, fluvoxamine, sertraline, paroxetine,citalopram, and escitalopram), venlafaxine, duloxetine, nefazodone,mianserin setiptiline, viqualine trazodone, cianopramine, andmirtazapine.

Phentermine is an example of a dopamine reuptake inhibitor with achemical name 2-methyl-1-phenylpropan-2-amine and 2-methyl-amphetamine.Throughout the present disclosure, whenever the term “phentermine” isused, it is understood that the term encompasses phentermine as a freebase, or as a physiologically acceptable salt thereof, or as aphentermine metabolite or salt thereof.

Antidiabetic

In some embodiments an antidiabetic includes, but is not limited to abiguanide, glucosidase inhibitor, insulin, meglitinide, sulfonylurea ora thiazolidinedione. In some embodiments a biguanide comprises metforminhydrochloride. In some embodiments a glucosidase inhibitor includes, butis not limited to acarbose and miglitol. Examples of insulin include,but are not limited to human insulin, pork insulin, beef insulin,beef-pork insulin, insulin from different sources such as recombinantDNA and animal sources, as well as regular, NPH, and LENTE® types ofinsulin. Other examples of insulin include, but are not limited tomixtures of the various forms of insulin (e.g. NPH and regular human andpork insulin). Other examples of insulin include mixtures of InsulinLispro Protamine and Insulin Injection (rDNA origin), a 50/50 (or a70/30) mixture of Human Insulin Isophane Suspension and Human InsulinInjection, a 70/30 mixture of NPH Human Insulin Isophane Suspension andHuman Insulin Injection (rDNA), insulin glargine, insulin lispro,insulin aspart, as well as insulin mixed with other ingredients such aszinc crystals or in a phosphate buffer. Insulin may be fromSaccharomyces cerevisiae or other sources. Examples of meglitinidesinclude, but are not limited to nateglinide and repaglinide. Examples ofsulfonylureas include, but are not limited to glimepiride, glyburide,glibenclamide, gliquidone, gliclazide, chlorpropamide, tolbutamide,tolazamide and glipizide. Examples of thiazolidinediones include, butare not limited to rosiglitazone and pioglitazone. Also included areextended release formulations of the above drugs, as well ascombinations of the above drugs and pharmaceutically acceptable salts orprodrugs thereof.

As mentioned above, in certain embodiments, the antidiabetic ismetformin. Metformin, whose chemical name is1-(diaminomethylidene)-3,3-dimethyl-guanidine, is often used in thetreatment of diabetes mellitus type 2, especially when accompaniedobesity and insulin resistance. Metformin has also been proven to reducethe cardiovascular complications of diabetes.

Anticonvulsants

In some embodiments, the anticonvulsant is selected from the groupincluding, but not limited to zonisamide, topiramate, nembutal,lorazepam, clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin,phenytoin, carbamazepine, balproate, felbamate, lebetiracetam,oxcarbazepine, lamotrigine, methsuximide and ethosuxmide.

Zonisamide is a marketed anticonvulsant indicated as adjunctive therapyfor adults with partial onset seizures. Without being bound by anyparticular theory, it is believed that the mechanism of antiepilepticactivity appears to be: (1) sodium-channel blocking; and (2) reductionof inward T-type calcium occurrence. In addition, zonisamide binds tothe GABA/benzodiazepine receptor complex without producing change inchloride flux. Further, zonisamide facilitates serotonergic anddopaminergic neurotransmission and possesses a weak inhibitory effect oncarbonic anhydrase.

Zonisamide has been shown to cause significant weight loss (comparableto marketed weight loss medications) in patients presenting primaryobesity. It has been postulated that the affect of zonisamide on the CNSconcentration of serotonin, dopamine and carbonic anhydrase isresponsible for this effect. There is evidence that zonisamide increasesserotonin and dopamine synthesis rates herein. There is further evidencesuggesting that zonisamide stimulates dopamine D₂ receptors.

Zonisamide can be formulated in a controlled- or sustained-releasetablet or gel form. This allows a patient newly prescribed zonisamide toramp up the dosage level over a period of several days. This increase indosage form allows the patient to avoid some of the negative sideeffects that have been exhibited during the initial administration ofzonisamide to a patient. Some of these initial side effects include ashock to the body. Although patients who start with a full dose ofzonisamide will become acclimated to the dosage over a period of time,the negative side effects accompanying the initial shock to the body canbe avoided with a method wherein dosages are increased over a period ofseveral days.

In a pharmaceutical composition with a drug such as bupropion, a methodof administering sustained-release zonisamide in a layered tablet canreduce shock to the body while maximizing bioavailability, and thus havea maximum effect for prevention of weight gain and/or treatment ofobesity.

Although the exact dosages will be determined on a drug-by-drug basis,in most cases some generalizations regarding the dosage can be made.Some descriptions of appropriate unit dosages of drugs including, butnot limited to bupropion, zonisamide, controlled-release zonisamide andcombinations thereof are disclosed in U.S. Provisional PatentApplication No. 60/740,034 entitled CONTROLLED RELEASE FORMULATION OFZONISIMIDE, filed on Nov. 28, 2005; and U.S. patent application Ser. No.11/194,202 entitled COMBINATION OF BUPROPION AND A SECOND COMPOUND FORAFFECTING WEIGHT LOSS, filed on Aug. 1, 2005; which are herebyincorporated by reference in their entireties, and U.S. PatentPublication Nos. 2005/0215552 and 2006/0079501 mentioned previously.

In some embodiments the anticonvulsant is a γ-amino butyric acid (GABA)inhibitor, a GABA receptor antagonist or a GABA channel modulator. By“GABA inhibitor” it is meant a compound that reduces the production ofGABA in the cells, reduces the release of GABA from the cells, orreduces the activity of GABA on its receptors, either by preventing thebinding of GABA to GABA receptors or by minimizing the effect of suchbinding. The GABA inhibitor may be a 5-HT1b agonist or another agentthat inhibits the activity of NPY/AgRP/GABA neurons. In addition, theGABA inhibitor may suppress the expression of the AgRP gene, or the GABAinhibitor may suppress the production or release of AgRP. It is,however, understood that a 5-HT1b agonist may inhibit the NPY/AgRP/GABAneuron (and therefore activate pro-opiomelanocortin (POMC) neurons)without acting as an inhibitor of the GABA pathway.

In certain other embodiments the GABA inhibitor increases the expressionof the POMC gene. In some of these embodiments, the GABA inhibitorincreases the production or release of POMC protein. In certain other ofthese embodiments, the GABA inhibitor increases the activity on POMCexpressing neurons.

In some embodiments, the GABA inhibitor is topiramate. Topiramate, whosechemical name is2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate, isoften used to treat epilepsy, Lennox-Gastaut syndrome (a disordercausing seizures and developmental delays), neuropathic pain, bipolardisorder, obesity including reduction of binge eating, alcoholism, PostTraumatic Stress Disorder, infantile spasm, bulimia nervosa, orobsessive-compulsive disorder or to assist smoking cessation or preventmigraines. Generally, initial doses of topiramate are low and increasedin slow steps. The usual initial dose is 25 to 50 mg daily in 2 singledoses. Recommended increments vary, but are usually between 25 mg and 50mg every 1 or 2 weeks. Common doses for maintenance treatment include,but are not limited to doses of approximately 100 to 200 mg daily.

Opioid Receptor Antagonists

In certain embodiments the opioid antagonist antagonizes a μ-opioidreceptor (MOP-R) in a mammal. The mammal may be selected from the groupincluding, but not limited to mice, rats, rabbits, guinea pigs, dogs,cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, andapes, and humans.

In some embodiments the opioid antagonist is selected from the groupincluding, but not limited to alvimopan, norbinaltorphimine, nalmefene,naloxone, naltrexone, methylnaltrexone, and nalorphine, andpharmaceutically acceptable salts or prodrugs thereof.

In other embodiments, the opioid antagonist is a partial opioid agonist.Compounds of this class have some agonist activity at opioid receptors.However, because they are weak agonists, they function as de-factoantagonists. Examples of partial opioid agonists include, but are notlimited to pentacozine, buprenorphine, nalorphine, propiram, andlofexidine.

Naltrexone (17-(cyclopropylmethly)-4, 5α-epoxy-3,14-dihydroxymorphinan-6-one), shown below, is an opioid receptorantagonist used primarily in the management of alcohol dependence andopioid dependence. μ-subtype selective opioid antagonists such asnaltrexone are also of considerable current interest as agents for thetreatment of obesity (Glass, M. J.; Billington, C. J.; Levine, A. S.Neuropeptides 1999, 33, 350) and CNS disorders (Reneric, J. P.; Bouvard,M. P. CNS Drugs 1998, 10, 365).

It is marketed as its hydrochloride salt, naltrexone hydrochloride,under the trade name REVIA™. REVIA™ is an immediate release formulationof naltrexone, with 100 mg strength. The maximum serum concentration ofimmediate release naltrexone is reached very rapidly, typically aT_(max) of approximately 1 hour. Immediate release naltrexone can induceside effects such as nausea, which is attributable to the maximum bloodplasma concentration levels (C_(max)).

An oral dosage form of naltrexone that is able to effect naltrexonerelease at a rate sufficiently slow to ameliorate side effects, yetsufficiently fast to achieve good bioavailability would provide asignificant improvement in dosing compliance and convenience. Likewise,an improved dosage form which lowered the incidence of gastrointestinalside-effects would also be of significant value.

In some embodiments, oral dosage forms of naltrexone are effective toprovide an AUC between about 75% to about 125% of 50 mg immediaterelease naltrexone tablets. In some embodiments oral dosage forms ofnaltrexone provide an amount of a retardant excipient that is effectiveto provide a C_(max) that is less than or equal to about 80% of theC_(max) of 50 mg immediate release naltrexone tablets.

Formulations of controlled- or sustained-release naltrexone have beendisclosed in U.S. Provisional Patent Application Ser. No. 60/811,251,filed Jun. 5, 2006, which is hereby incorporated by reference in itsentirety. In some embodiments, oral dosage forms of naltrexone areeffective to provide an AUC between about 75% to about 125% of 50 mgimmediate release naltrexone tablets. In some embodiments oral dosageforms of naltrexone comprise an amount of a retardant excipient that iseffective to provide a C_(max) that is less than or equal to about 80%of the C_(max) of 50 mg immediate release naltrexone tablets.

Those skilled in the art informed by the guidance provided herein canformulate oral dosage forms described herein. For example, one skilledin the art could formulate an oral dosage form that includes, but is notlimited to an amount of naltrexone effective to provide an AUC betweenabout 75% to about 125% of 50 mg immediate release naltrexone tablets,and an amount of an appropriate retardant excipient effective to providea C_(max) that is less than or equal to about 80% of the C_(max) of 50mg immediate release naltrexone tablets. Further, given the guidanceprovided herein, the skilled artisan could formulate an oral dosage formhaving a pharmacodynamic profile characterized by coverage of greaterthan or equal to 80% of the opioid receptors in the hypothalamus.

EXAMPLES

Below are found specific examples of pharmaceutical compositions thatmay be formed into layered pharmaceutical formulations of the presentdisclosure.

TABLE 1 Formulations for Sustained-Release (SR) Tablets ContainingBupropion 70 mg 90 mg Bupropion SR Bupropion SR Amount per Amount perIngredient Tablet Tablet Bupropion HCL, USP 70.0 mg 90.0 mgMicrocrystalline Cellulose, NF 173.3 mg 153.3 mg (Avicel PH 101)Hydroxypropyl Cellulose, NF 56.7 mg 56.7 mg (Klucel HXF) Cysteine HCL,NF 12.5 mg 12.5 mg Magnesium Stearate, NF 2.5 mg 2.5 mg Tablet Weight315.0 mg 315.0 mg

TABLE 2 Formulations for Sustained-Release (SR) Tablets ContainingZonisamide 30 mg 60 mg 90 mg Zonisamide SR Zonisamide SR Zonisamide SRAmount per Amount per Amount per Ingredient Tablet Tablet TabletZonisamide 30 mg 60 mg 90 mg Klucel 110 mg 35 mg 35 mg Lactose 55 mg 70mg 60 mg Colloidal Silicon 2 mg 2 mg 2 mg Dioxide, NF Cross Povidone 20mg 14 mg 14 mg Magnesium 6 mg 6 mg 6 mg Stearate, NF Microcrystalline127 mg 163 mg 143 mg Cellulose, NF

TABLE 3 Formulations for Sustained -Release (SR) Tablets ContainingNaltrexone Percent per Percent per Percent per Tablet “12.5% Tablet “30%Tablet “44% HPMC” HPMC” HPMC” Ingredient SR-Fast SR-Medium SR-SlowNaltrexone 6.667 6.667 6.667 (5 mg) Hydroxypropylmethyl 10.000 30.00044.333 Cellulose (Methocel K15 Premium) Common QBQ01 Placebo 81.73361.833 47.500 Granulation Colloidal Silicon 1.000 0.500 1.000 Dioxide,NF (Cab-O-Sil M5P) Sodium Edetate 0.1 — — Magnesium Stearate, NF, 0.5006.667 0.500 Ph. Eur. (Vegetable Source) (Grade 905-G) 100.000 100.000100.000

Thus, as illustrated in Tables 1-3 above, embodiments of pharmaceuticalformulations may comprise controlled-release (e.g., sustained release inthe illustrated embodiments) formulations of bupropion, zonisamideand/or naltrexone. In one embodiment, a layered pharmaceuticalformulation is a tablet comprising a first layer comprising acontrolled-release zonisamide and a second layer comprising a bupropion.In another embodiment a layered pharmaceutical formulation is a tabletcomprising a first layer comprising a controlled-release naltrexone anda second layer comprising a controlled-release bupropion. In someembodiments the first layer and the second layer are separated by anintermediate layer comprising lactose or other suitable fast-dissolvingingredient.

The oral dosage forms of pharmaceutical formulations can, if desired, bepresented in a unit dosage package which may contain one or more unitdosage forms containing the active ingredient. The unit dosage packagemay for example comprise metal or plastic foil, such as a blister pack.The unit dosage package may be accompanied by instructions foradministration. The unit dosage package may also be accompanied with anotice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchnotice, for example, may be the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. Compositions comprising a compound of the disclosure formulatedin a compatible pharmaceutical carrier may also be prepared, placed inan appropriate container, and labeled for treatment of an indicatedcondition. Novel methods and systems for administering weight lossmedications are described in co-pending application entitled METHODS FORADMINISTERING WEIGHT LOSS MEDICATIONS filed on the same day as thepresent application, which is hereby incorporated by reference in itsentirety.

In some embodiments, the weight loss medications are provided at leastonce, twice or three times a day for a set period, which can be atleast, at least about, less than, less than about, equal to or betweenany range within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutivedays or at least, at least about, less than, less than about, equal toor between any range within of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or30 consecutive weeks or at least, at least about, less than, less thanabout, equal to or between any range within 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 consecutive months. The amount of drug in anypharmaceutical formulation described herein includes, but is not limitedto amounts of at least, at least about, less than, less than about,equal to or between any range within 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000,3000, 4000 or 5000 mg.

In one embodiment a layered pharmaceutical formulation for theadministration of two or more active pharmaceutical ingredientscomprises a first pharmaceutical layer comprising a first activepharmaceutical ingredient, a second pharmaceutical layer comprising asecond active pharmaceutical ingredient and at least one intermediatelayer disposed between the first and the second pharmaceutical layers,wherein the at least one intermediate layer is configured to dissolve invivo to thereby leave the first and the second pharmaceutical layerssubstantially intact.

In some embodiments each of the first and the second pharmaceuticallayers comprises a dissolution profile substantially similar to asingularly compressed tablet of a similar composition. In someembodiments each of the first and the second pharmaceutical layerscomprises a different pharmaceutical composition. In some embodiments atleast one of the first and the second pharmaceutical layers comprises acontrolled-release pharmaceutical composition. In some embodiments thecontrolled-release pharmaceutical composition comprises a sustainedrelease pharmaceutical composition.

In some embodiments at least one of the first and the secondpharmaceutical layers comprises zonisamide. In some embodiments thezonisamide comprises a controlled-release zonisamide. In someembodiments the controlled-release zonisamide comprises asustained-release zonisamide. In some embodiments at least one of thefirst and the second pharmaceutical layers comprises bupropion. In someembodiments the bupropion comprises a controlled-release bupropion. Insome embodiments the controlled-release bupropion comprises asustained-release bupropion. In some embodiments at least one of thefirst and the second pharmaceutical layers comprises naltrexone. In someembodiments at least one of the first and the second pharmaceuticallayers comprises fluoxetine.

In some embodiments at least one of the first and the secondpharmaceutical layers comprises olanzapine. In some embodiments at leastone of the first and the second pharmaceutical layers comprises anantidiabetic. In some embodiments the antidiabetic comprises metformin.In some embodiments at least one of the first and the secondpharmaceutical layers comprises topiramate. In some embodiments at leastone of the first and the second pharmaceutical layers comprisesphentermine. In some embodiments the at least one intermediate layercomprises at least one of a monosaccharide sugar, a disaccharide sugar,or a starch. In some embodiments the at least one intermediate layercomprises lactose.

In one embodiment a method for affecting weight loss, suppressingappetite and/or treating an obesity-related condition in a patientcomprises providing a first dosage of the layered pharmaceuticalformulation to a patient in need thereof on a first day and providing asecond dosage of the layered pharmaceutical formulation to the patienton a second day. In some embodiments the first dosage is greater thanthe second dosage. In some embodiments the second dosage is greater thanthe first dosage.

In one embodiment a method for treating an obesity related condition ina patient comprises identifying a patient with an obesity relatedcondition or at risk of an obesity related condition comprises providinga first dosage of the layered pharmaceutical formulation of claims 1 tothe patient on a first day and providing a second dosage of the layeredpharmaceutical formulation to the patient on a second day. In someembodiments the first dosage is different than the second dosage. Insome embodiments the second dosage is greater than the first dosage.

In one embodiment use of a first compound and a second compound in theformulation of a medicament for affecting weight loss, suppressingappetite or treating an obesity-related condition, wherein themedicament comprises a layered pharmaceutical formulation of the presentinvention.

It will be appreciated by those skilled in the art that variousmodifications and changes can be made without departing from the scopeof the disclosure. Such modifications and changes are intended to fallwithin the scope of the disclosure, as defined by the appended claims.

What is claimed is:
 1. A layered pharmaceutical formulation for theadministration of two or more active pharmaceutical ingredientscomprising: a first pharmaceutical layer comprising a first activepharmaceutical ingredient; a second pharmaceutical layer comprising asecond active pharmaceutical ingredient; and an intermediate layerdisposed between said first and said second pharmaceutical layers,wherein said intermediate layer is configured to rapidly dissolve invivo, and thereby leave said first and said second pharmaceutical layerssubstantially intact but physically separated.
 2. The layeredpharmaceutical formulation of claim 1, wherein each of said first andsaid second pharmaceutical layers comprises a dissolution profilesubstantially similar to a singularly compressed tablet of a similarcomposition.
 3. The layered pharmaceutical formulation of claim 1,wherein each of said first and said second pharmaceutical layerscomprises a different pharmaceutical composition.
 4. The layeredpharmaceutical formulation of claim 1, wherein at least one of saidfirst and said second pharmaceutical layers comprises acontrolled-release pharmaceutical composition.
 5. The layeredpharmaceutical formulation of claim 4, wherein said controlled-releasepharmaceutical composition comprises a sustained release pharmaceuticalcomposition.
 6. The layered pharmaceutical formulation of claim 1,wherein at least one of said first and said second pharmaceutical layerscomprises zonisamide.
 7. The layered pharmaceutical formulation of claim6, wherein said zonisamide comprises a controlled-release zonisamide. 8.The layered pharmaceutical formulation of claim 7, wherein saidcontrolled-release zonisamide comprises a sustained-release zonisamide.9. The layered pharmaceutical formulation of claim 6, wherein said firstlayer comprises zonisamide, and said second layer comprises bupropion.10. The layered pharmaceutical formulation of claim 1, wherein at leastone of said first and said second pharmaceutical layers comprisesbupropion.
 11. The layered pharmaceutical formulation of claim 9,wherein said bupropion comprises a controlled-release bupropion.
 12. Thelayered pharmaceutical formulation of claim 11, wherein saidcontrolled-release bupropion comprises a sustained-release bupropion.13. The layered pharmaceutical formulation of claim 1, wherein at leastone of said first and said second pharmaceutical layers comprisesnaltrexone.
 14. The layered pharmaceutical formulation of claim 13,wherein said naltrexone comprises a controlled-release naltrexone. 15.The layered pharmaceutical formulation of claim 14, wherein saidcontrolled-release naltrexone comprises a sustained-release naltrexone.16. The layered pharmaceutical formulation of claim 13, wherein saidfirst layer comprises naltrexone, and said second layer comprisesbupropion.
 17. The layered pharmaceutical formulation of claim 1,wherein at least one of said first and said second pharmaceutical layerscomprises fluoxetine.
 18. The layered pharmaceutical formulation ofclaim 17, wherein said first layer comprises fluoxetine and said secondlayer comprises naltrexone.
 19. The layered pharmaceutical formulationof claim 1, wherein at least one of said first and said secondpharmaceutical layers comprises olanzapine.
 20. The layeredpharmaceutical formulation of claim 19, wherein said first layercomprises olanzapine and said second layer comprises zonisamide.
 21. Thelayered pharmaceutical formulation of claim 1, wherein at least one ofsaid first and said second pharmaceutical layers comprises anantidiabetic.
 22. The layered pharmaceutical formulation of claim 21,wherein said antidiabetic comprises metformin.
 23. The layeredpharmaceutical formulation of claim 22, wherein said first layercomprises metformin, and said second layer comprises zonisamide.
 24. Thelayered pharmaceutical formulation of claim 1, wherein at least one ofsaid first and said second pharmaceutical layers comprises topiramate.25. The layered pharmaceutical formulation of claim 1, wherein at leastone of said first and said second pharmaceutical layers comprisesphentermine.
 26. The layered pharmaceutical formulation of claim 25,wherein said first layer comprises phentermine, and said second layercomprises topiramate.
 27. The layered pharmaceutical formulation ofclaim 1, wherein said intermediate layer comprises at least one of amonosaccharide sugar, a disaccharide sugar, or a starch.
 28. The layeredpharmaceutical formulation of claim 27, wherein said at least oneintermediate layer comprises lactose.
 29. A method for affecting weightloss in a patient comprising: identifying a patient in need of weightloss; providing a first dosage of the layered pharmaceutical formulationof claim 1 to a patient in need thereof on a first day; and providing asecond dosage of the layered pharmaceutical formulation to the patienton a second day, wherein said layered pharmaceutical formulationcomprises a first layer comprising bupropion and a second layercomprising zonisamide or naltrexone.
 30. The method of claim 29, whereinsaid first dosage is greater than said second dosage.
 31. The method ofclaim 29, wherein said second dosage is greater than said first dosage.32. A method for treating an obesity related condition in a patientcomprising: identifying a patient suffering from or at risk of anobesity related condition; providing a first dosage of the layeredpharmaceutical formulation of claim 1 to the patient on a first day; andproviding a second dosage of the layered pharmaceutical formulation tothe patient on a second day, wherein said layered pharmaceuticalformulation comprises a first layer comprising bupropion and a secondlayer comprising zonisamide or naltrexone.
 33. The method of claim 32,wherein said first dosage is different than said second dosage.
 34. Themethod of claim 32, wherein said second dosage is greater than saidfirst dosage.